Tumour suppressor genes function by restraining cell cycle progression, maintaining genomic integrity or promoting apoptosis.
Chromosomal imbalances are often observed in haematological malignancies and somatic deletions are believed to indicate the location of tumour suppressor genes whose alteration produces loss-of-function in a recessive (Knudson's model) or haploinsufficient (the inactivation of one allele is sufficient to change the phenotype of one cell) context.
The inventors have previously described the occurrence and persistence of hemizigous 6q13-q22 deletions in abnormal CD3-CD4+ T cell clones from two patients suffering from the lymphocytic variant of the hypereosinophilic syndrome (L-HES) over a 6-year study period during which one patient developed a T-cell lymphoma (RAVOET, M. ET AL., 2009. Blood. 114(14), 2969-2983).
Recurrent finding of 6q deletions in various solid tumours and lymphoid diseases has suggested the presence of several tumour suppressor genes residing on the long arm of chromosome 6. The first evidence that 6q loci are involved in tumour suppression came from somatic cell hybrid experiments inducing senescence in fibroblasts and from microcell-mediated chromosome 6 transfer within breast and ovarian cancer cell lines.
Despite heterogeneity, several studies refining the regions of minimal deletion (RMD) in large patient cohorts with lymphoid malignancies highlighted preferential loss of 4 distinct regions at bands 6q14-q15, 6q16-q21, 6q23 and 6q25-27. Notably, deletions of chromosomal bands 6q16-21 are preferentially associated with all of T-lineage and high-grade prostate cancers.
With recent advances in high resolution array-based comparative genomic hybridization (aCGH), a growing number of 6q tumour suppressor genes (such as GRIK2, HACE1, PRDM1, SESN1, REV3L, PTPRK, TNFAIP3/A20, PARK2, . . . ) have been identified at different loci as potential candidates for specific diseases. However, with the exception of the TNFAIP3 (A20) gene, located at band 6q23 and recently recognized as a tumour suppressor gene of B-lineage lymphomas subsets, no definitive evidence of suppressive activity has been obtained for other 6q gene-locus candidates in separate entities.
In human, BTB and CNC homolog 1, basic leucine zipper transcription factor 2 (BACH2) is located at 6q15. This gene is expressed mostly in the thymus, the spleen and leukocytes and at a lower level in the small intestine and the brain. BACH2 mRNA is notably present in pre-B lymphocytes and expressed up to fourfold more strongly in cord blood (UCB) and naïve CD4+CD45RA+ T cells compared to adult CD4+ T cells.
As measured after immunohistochemical analysis, level 2 expression of BACH2 protein represents a worse prognosis for a particular subset of patients suffering from B-cell lymphoma treated with doxorubicin (with no more disclosure about treatment predictivity). The quantification of BACH2 mRNA in the same subsets of patients shows a reduction in the level 2 group, albeit not reaching statistical significance, pointing to the difficulty of analyses based on mRNA quantification of mixture of cancerous cells with non-neoplastic cells (SAKANE-ISHIKAWA ET AL., J. Clin. Oncol. 2005, 23, 8012-8017) and/or to differences between morphological and merely quantitative methods.